Abstract
Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 6172 |
| Tidsskrift | Nature Communications |
| Vol/bind | 14 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:For this work, A.B.-A., S.J.B. and L.P. were funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 821511 (BIOMAP). The J.U. receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author’s view and the J.U. is not responsible for any use that may be made of the information it contains. A.B.A., M.K.S., J.L.M., and L.P. and work in a research unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4). LP received funding from the British Skin Foundation (8010 Innovative Project) and the Academy of Medical Sciences Springboard Award, which is supported by the Wellcome Trust, The Government Department for Business, Energy and Industrial Strategy, the Global Challenges Research Fund and the British Heart Foundation [SBF003\1094]. S.J.B. holds a Wellcome Trust Senior Research Fellowship in Clinical Science [220875/Z/20/Z]. S.H. is supported by a Vera Davie Study and Research Sabbatical Bursary, NRF Thuthuka Grant (117721), NRF Competitive Support for Unrated Researcher (138072), MRC South Africa under a Self-initiated grant. M.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 949906). Thanks to Sergi Sayols (developer of rrvgo), who provided additional code to alter the scatter plot produced by rrvgo to only display parent terms, and to Gibran Hemani (University of Bristol) who provided valuable guidance on the comparison of effects between ancestries. This publication is the work of the authors and LP will serve as guarantor for the contents of this paper. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol— http://www.bristol.ac.uk/acrc/ . Individual cohort acknowledgements are in the Supplementary Methods.
Funding Information:
For this work, A.B.-A., S.J.B. and L.P. were funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 821511 (BIOMAP). The J.U. receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author’s view and the J.U. is not responsible for any use that may be made of the information it contains. A.B.A., M.K.S., J.L.M., and L.P. and work in a research unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4). LP received funding from the British Skin Foundation (8010 Innovative Project) and the Academy of Medical Sciences Springboard Award, which is supported by the Wellcome Trust, The Government Department for Business, Energy and Industrial Strategy, the Global Challenges Research Fund and the British Heart Foundation [SBF003\1094]. S.J.B. holds a Wellcome Trust Senior Research Fellowship in Clinical Science [220875/Z/20/Z]. S.H. is supported by a Vera Davie Study and Research Sabbatical Bursary, NRF Thuthuka Grant (117721), NRF Competitive Support for Unrated Researcher (138072), MRC South Africa under a Self-initiated grant. M.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 949906). Thanks to Sergi Sayols (developer of rrvgo), who provided additional code to alter the scatter plot produced by rrvgo to only display parent terms, and to Gibran Hemani (University of Bristol) who provided valuable guidance on the comparison of effects between ancestries. This publication is the work of the authors and LP will serve as guarantor for the contents of this paper. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol—http://www.bristol.ac.uk/acrc/. Individual cohort acknowledgements are in the Supplementary Methods.
Publisher Copyright:
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